Mechanismen der Tachyphylaxie bei langdauernden Regionalanästhesien

E. Kottenberg-Assenmacher; J. Peters

doi:10.1055/s-1999-228

AINS - Anästhesiologie · Intensivmedizin · Notfallmedizin · Schmerztherapie, Table of Contents

Anästhesiol Intensivmed Notfallmed Schmerzther 1999; 34(12): 733-742
DOI: 10.1055/s-1999-228

DER BESONDERE BEITRAG

Georg Thieme Verlag Stuttgart ·New York

Mechanismen der Tachyphylaxie bei langdauernden Regionalanästhesien

Mechanisms of Tachyphylaxia in Regional Anesthesia of Long Duration.E. Kottenberg-Assenmacher, J. Peters

Abteilung für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen

Abstract

Zusammenfassung.

Tachyphylaxie von Lokalanästhetika wird klinisch definiert als abnehmende Intensität, abnehmende Wirkdauer und abnehmende segmentale Ausdehnung einer Nervenblockade nach wiederholten, gleichgroßen Dosen eines Lokalanästhetikums. Die Häufigkeit des Auftretens von Tachyphylaxie wird kontrovers beurteilt. Da allerdings kaum anzunehmen ist, daß eine Tachyphylaxie tatsächlich mit wechselnder Häufigkeit auftritt, scheint am ehesten die Interpretation von Tachyphylaxie durch den Untersucher unterschiedlich zu sein. Abzugrenzen ist die „Pseudotachyphylaxie”, nämlich zeitliche Änderungen der Schmerzintensität sowie zirkadiane Schwankungen der Wirkdauer von Lokalanästhetika, die eine Tachyphylaxie vortäuschen. Das Auftreten von Tachyphylaxie hängt weder von der chemischen Struktur oder dem pharmakologischen Wirkprofil des injizierten Lokalanästhetikums noch von der Technik oder der Art der Applikation ab. Als mögliche Mechanismen der Tachyphylaxie werden pharmakokinetische und pharmakodynamische Aspekte diskutiert. Unter pharmakokinetischem Blickwinkel können perineurale Ödembildung, Anstieg der Proteinkonzentration im Periduralraum, veränderte Verteilung des Lokalanästhetikums im Periduralraum oder Abfall des perineuralen pH-Wertes Ursachen für eine verringerte Diffusion des Lokalanästhetikums zum Natriumkanalrezeptor sein. Ursachen einer erhöhten Clearance des Lokalanästhetikums können sowohl zunehmende peridurale Perfusion als auch ein lokal gesteigerter Metabolismus im Periduralraum sein. Unter pharmakodynamischen Aspekten müssen ein funktioneller Antagonismus der Lokalanästhetika durch Nukleotide, ein Antagonismus durch einen vergrößerten Natriumgradienten, eine Steigerung der zentralen Erregbarkeit sowie eine Rezeptor-Down-Regulation der Natriumkanäle diskutiert werden. Keiner der aufgeführten Mechanismen kann jedoch zur Zeit das Phänomen der Tachyphylaxie allein hinreichend erklären. Als neue Möglichkeit, eine reversible Nervenblockade länger aufrechtzuerhalten, werden neue, ultralangwirksame Lokalanästhetika getestet. Denkbar ist eine Weiterentwicklung der hochselektiven Natriumkanalblockade durch Analoga des Kugelfischgiftes Tetrodotoxins sowie der Einsatz Lokalanästhetikahaltiger Liposomen. Ein neuer erfolgversprechender Ansatz liegt in dem Befund, daß sowohl NMDA-Antagonisten als auch NO-Synthase-Inhibitoren die Entwicklung von Tachyphylaxie verhindern. Wäre NO tatsächlich für die Tachyphylaxie verantwortlich, so hätte man damit mögliche Substanzen gefunden, mit denen eine Tachyphylaxie verhindert werden könnte.

Tachyphylaxis to local anesthetics is defined as a decrease in duration, segmental spread or intensity of a regional block despite repeated constant dosages. However, there is disagreement about the incidence of tachyphylaxis. In contrast to tachyphylaxis, pseudotachyphylaxis denotes time dependent variations in pain or circadian changes in the duration of local anesthetic action. Tachyphylaxis appears neither to be linked to structural or pharmacological properties of the local anesthetics nor to the technique or mode of their administration. The mechanisms underlying tachyphylaxis are open to debate and include changes in pharmacokinetics or pharmacodynamics. Considering pharmacokinetics, local edema, an increased epidural protein concentration, changes in local anesthetic distribution in the epidural space or a decrease of perineural pH could result in decreased diffusion of the local anesthetics from the epidural space to their binding sites at the sodium channel. Increased clearance of local anesthetics from the epidural space may be caused both by increased epidural blood flow or increased local metabolism. Considering pharmacodynamics, antagonistic effects of nucleotides or increased sodium concentration, increased afferent input from nociceptors or receptor down regulation of the sodium channels have been implicated. However, none of these theoretical considerations is supported strongly enough by data to explain tachyphylaxis. A new possibility to maintain for a longer time neural blockade is the design of new ultralong-acting local anesthetics. Liposomal formulations of local anesthetics also appear suitable to provide longer lasting regional anesthesia. The recent observation that NMDA-antagonists as well as NO-synthase-inhibitors prevent the development of tachyphylaxis suggests involvement of the nitric oxide pathway in the development of tachyphylaxis. Accordingly, NMDA-antagonists or NO-synthase-inhibitors may prevent tachyphylaxis.

Schlüsselwörter:

Tachyphylaxie - Lokalanästhetika - NO

Key words:

tachyphylaxis - local anaesthetics - nitric oxide

Full Text

References

Literatur

1 Champy C, Gley E. Sur la toxicitÅ des extraits de corps jaune. Immunisation rapide consecutive a l'injection de petits doses de ces extraits (tachyphylaxie). CR Soc Biol (Paris). 1911; 71 159-163
2 Ariens E J, Simonis A M. A molecular basis for drug action. The interaction of one or more drugs with different receptors. J. Pharm. Pharmacol.. 1964; 16 289-295
3 McQuay H J, Bullingham R ES, Moore R A. Acute opiate tolerance in man. Life Sci.. 1981; 28 2513-2517
4 Brodie B B, Mark L C, Lief P A, Bernstein E, Papper E M. Acute tolerance to thiopental. J. Pharmacol. Exp. Ther.. 1951; 102 215-221
5 Bromage P R. Epidural analgesia. WB Saunders, Philadelphia, London, Toronto 1978: 100-105
6 Bromage P R, Pettigrew R T, Crowell D E. Tachyphylaxis in epidural analgesia: I. Augmentation and decay of local anesthesia. J. Clin. Pharmacol.. 1969; 9 30-38
7 Knapp D E. Tolerance development to a local anesthetic effect of meperidine. J. Oral. Ther. Pharmacol.. 1968; 4 364-368
8 Mather L E. Tachyphylaxis in reginal anesthesia: Can we reconcile clinical observations and laboratory measurements? In: Wüst HJ, Stanton-Hicks M (eds): New aspects in regional anesthesia, Vol. 4. Springer, Berlin, Heidelberg, New York 1986: 3-15
9 Truant A P, Takman B. Local anesthetics. In: Di-Palma JR (ed): Drill's pharmacology in medicine. McGraw-Hill, New York 1965: 133-142
10 Bryce-Smith R, Williams E O. The treatment of eclampsia (imminent or actual) by continuous conduction analgesia. Lancet. 1955; 1 1241-1243
11 Bromage P R. Spirometry in assesment of analgesia after abdominal surgery. Brit. Med. J.. 1955; 2 589-595
12 Muneyuki M, Ueda Y, Urabe N, Kato H, Shirai K, Inamato A. Oxygen breathing and shunting during postoperative pain relief in man. Canad. Anaesth. Soc. J.. 1972; 19 230-238
13 Sjögren S, Wright B. Circulation, respiration and lidocaine concentration during continuous epidural blockade. Acta. Anaesthesiol. Scand.. 1972; 16 5
14 Moding J. Respiration and circulation after total hip replacement surgery. A comparison between parenteral analgesics and continuous lumbal epidural block. Acta anaesth. scand.. 1976; 20 225-236
15 Wüst H J, Florack G, Lennartz H. Kreislaufveränderungen während und nach aorto-femoralen Bypassoperationen (AFB) unter kontinuierlicher Epiduralanästhesie. Langenbecks Arch. Chir.. 1976; 342 594-600
16 Wüst H J, Sandmann W, Lennartz H. Postoperative Analgesie mit der kontinuierlichen Epiduralanalgesie und mit Dolantin. Langenbecks Arch. Chir.. 1976; 342 393-398
17 Wüst H J, Sandmann W, Richter I. Hämodynamische Veränderungen durch Schmerzphasen infolge Tachyphylaxie bei postoperativer Epiduralanaesthesie. In: Wüst HJ, Zindler M (Hrsg): Neue Aspekte in der Regionalanaesthesie, Bd 1. Springer, Berlin, Heidelberg, New York 1980: 89-85
18 Brown W E. Single injection caudal for obstetrical analgesia and the use of pontocaine. Am. J. Obstet. Gynecol.. 1948; 55 717-722
19 Cox J MR, Spoerel W E. Continuous epidural analgesia - the use of an intermittent injection device. Can. Anaesth. Soc. J.. 1964; 11 72-77
20 Hjortso N C, Lund C, Mogensen T, Bigler D, Kehlet H. Epidural morphine improves pain relief and maintains sensory analgesia during continuous epidural bupivacaine after abdominal surgery. Anesth. Analg.. 1986; 65 (10) 1033-1036
21 Wüst H J, Richter O, Strasser K. Tachyphylaxie bei kontinuierlicher thorakaler Epiduralanalgesie mit Bupivacain 0,125 % und 0,25 %. Anaesth. Intensivther. Notfallmed.. 1980; 15 159-165
22 Wüst H J. Clinical observation of tachyphylaxis during long-term epidural analgesia. In: Wüst HJ, Stanton-Hicks M (eds): New Aspects in Regional Anesthesia, Vol 4. Springer, Berlin, Heidelberg, New York 1986: 24-30
23 Moir D D, Willocks J. Continuous epidural analgesia in incoordinate uterine action. Acta Anaesthesiol. Scand. (Suppl). 1966; 23 144-153
24 Simcock M J. Bupivacaine for regional analgesia in labour. A double-bind comparison with lignocaine. Med. J. Aust.. 1970; 2 889-891
25 Spoerel W E, Thomas A, Gerula G R. Continuous epidural analgesia: experience with mechanical injection device. Can. Anaesth. Soc. J.. 1970; 17 37-51
26 Hanson B, Matouskova-Hanson A. Continuous epidural analgesia for vaginal delivery in Sweden - Report of a nationwide inquiry. Acta Anaesthesiol. Scand.. 1985; 29 712-715
27 Holmdahl M H, Sjögren S, Ström G, Wright B. Clinical aspects of continuous epidural blockade for postoperative pain relief. Ups. J. Med. Sci.. 1972; 77 47-56
28 Matouskova A, Hanson B. Continuous mini-infusion of bupivacaine into the epidural space during labor. Part II: Blood concentration of bupivacaine. Acta Obstet. Gynecol. Scand.. 1979; 83 43-52
29 Pflug A E, Murphy T M, Butler S H, Tucker G T. The effects of postoperative peridural analgesia on pulmonary therapy and pulmonary complications. Anesthesiology.. 1974; 41 8-17
30 Raj P P, Denson D D, De Jong R H. No tachyphylaxis with prolonged, continuous bupivacaine. In: Wüst HJ, Stanton-Hicks M (eds): New aspects in regional anesthesia, Vol 4. Springer, Berlin, Heidelberg, New York 1986: 10-19
31 Raj P P, Knarr D C, Vigdorth E, Denson D D, Pither C E, Hartrick C T, Hopson C N, Edström H H. Comparison of continuous epidural infusion of a local anesthetic and administration of systemic narcotics in the management of pain after total knee replacement surgery. Anesth. Analg.. 1987; 66 401-406
32 Scott D B. Tachyphylaxis and local anesthetics. In: Wüst HJ, Stanton-Hicks M (eds): New aspects in regional anesthesia, vol 4. Springer, Berlin, Heidelberg, New York 1986: 20-27
33 Stanton-Hicks M. A study using bupivacaine for continuous peridural analgesia in patients undergoing surgery of the hip. Acta Anaesthesiol. Scand.. 1971; 15 97-106
34 Renck H. Tachyphylaxis during postoperative peridural analgesia of long action. In: Wüst HJ, Zindler M (Hrsg): Neue Aspekte in der Regionalanästhesie, Bd 1. Springer, Berlin, Heidelberg, New York 1980: 188-196
35 Gjessing J, Tomlin P J. Patterns of postoperative pain. A study of the use of continuous epidural analgesia in the postoperative period. Anaesthesia.. 1979; 34 624-623
36 Cohen E N, Levine D A, Collis J E, Gunther R E. The role of pH in the development of tachyphylaxis to local anesthetic agents. Anesthesiology. 1968; 29 994-1001
37 Spintge R, Droh R. Erste Untersuchungen zur Chronopharmakologie in der postoperativen Schmerzbehandlung. Schmerz-Pain-Douleur. 1986; 7 22-25
38 Reinberg A, Reinberg M A. Circadian changes of the duration of action of local anaesthetics agents. Naunyn-Schmiedeberg's Arch. Pharmacol.. 1977; 297 149-152
39 Mogensen T. Tachyphylaxis to epidural local anaesthetics. Dan. Med. Bull.. 1995; 42 141-146
40 Armitage E N. Local anaesthetic techniques for prevention of postoperative pain. Br. J. Anaesth.. 1986; 58 790-800
41 Duthie A M, Wyman J B, Lewis G A. Bupivacaine in labour. Its use in lumbar extradural analgesia. Anaesthesia. 1968; 23 20-26
42 Moir D D. Recent advances in pain relief in childbirth. II. Regional anaesthesia. Br. J. Anaesth.. 1971; 43 849-863
43 Poppers P J. Tachyphylaxis to local anesthetic agents. In: Poppers PJ, Van Dijk B (eds): Advances in regional anaesthesia. Proceedings of the International Symposium on Local Anaesthetics and Regional Anaesthesia. The Haque 1977: 79-85
44 Smith S M, Rees V L. The use of prolonged continuous spinal anaesthesia to relieve vasospasm and pain in peripheral embolism. Anesthesiology. 1948; 9 229-234
45 Tucker G T, Mather L E. Pharmacology of local anaesthetic agents - Pharmacocinetics of local anaesthetic agents. Br. J. Anaesth.. 1975; 47 213-224
46 Covino B. Pharmacology of local anaesthetic agents. Br. J. Anaesth.. 1986; 58 701-716
47 Hornburg D. Versuche über die Möglichkeit einer Gewöhnung an lokalanästhetische Effekte. Inauguraldissertation Hannover, Tierärztliche Hochschule 1960
48 Pizzolato P, Renegar O J. Histopathologic effects of long exposure to local anesthetics on peripheral nerves. Anesth. Analg.. 1959; 38 138-141
49 Selander D, Brattsand R, Lindborg G, Nordborg C, Olsson Y. Local anesthetics: Importance of mode of application, concentration and adrenaline for the appearance of nerve lesions. Acta Anaesthesiol. Scand.. 1979; 23 127-136
50 Myers R R, Kalichman M W, Reisner L S, Powell H C. Neurotoxity of local anesthetics: Altered perineural permeability, edema and nerve fiber injury. Anesthesiology. 1986; 64 29-35
51 Mogensen T, Simonsen L, Scott N B, Henriksen J H, Kehlet H. Tachyphylaxis associated with repeated epidural injections of lidocaine is not related to changes in distribution or the rate of elimination from the epidural space. Anesth. Analg.. 1989; 69 180-184
52 Ritchie J M, Ritchie B, Greengard B. The effects of the nerve sheath on the action of local anesthetics. J. Pharmacol. Exp. Ther.. 1965; 150 160-165
53 Stark P, Gergs P, Nolte H. Die pH-Veränderungen des Liquor spinalis durch Bupivacain. Anästhesist. 1977; 26 395-397
54 Kamaya H, Hayes J J, Ueda I. Dissociation constants of local anesthetics and their temperature dependence. Anesth. Analg.. 1983; 62 1025-1030
55 Adams H J. Effect of pH on spinal anesthesia with lidocaine in sheep. Pharmacol. Res. Commun.. 1975; 7 551-555
56 Adams H J, Charron D M, Takman B H. Spinal anesthesia in sheep with local anesthetic solutions at pH 4 and pH 7. Acta Anaesthesiol. Scand.. 1984; 28 270-272
57 Reynolds F, Bryson T HL, Nicholas A DG. Intradermal study of a new local anaesthetic agent: aptocaine. Br. J. Anaesth.. 1976; 48 347-354
58 Lebeaux M I. Experimental epidural anaesthesia in the dog with lignocaine and bupivacaine. Br. J. Anaesth.. 1973; 45 549-555
59 Renck H, Edström H, Kinnberger B, Brandt G. Thoracic epidural analgesia. II. Prolongation in the early postoperative period by continuous injection of 1.0 % bupivacaine. Acta Anaesthesiol. Scand.. 1976; 20 47-56
60 Renck H, Edström H. Thoracic epidural analgesia. III: Prolongation in the early postoperative period by intermittent injections of etidocaine with adrenaline. Acta Anaesthesiol. Scand.. 1976; 20 104-110
61 Wüst H J, Abels J, Thiessen F MM, Breulmann M, Schier R, Richter O. Plasma levels of bupivacaine under continuous thoracic epidural anesthesia and analgesia. In: Wüst HJ, Stanton-Hicks M, Zindler M (Hrsg): Neue Aspekte in der Regionalanästhesie, Bd.3. Springer, Berlin, Heidelberg, New York 1984: 24-32
62 Mogensen T, Hojgaard L, Scott N B, Henriksen J H, Kehlet H. Epidural blood flow and regression of sensory analgesia during continuous postoperative epidural infusion of bupivacaine. Anesth. Analg.. 1988; 67 809-813
63 Skagen K, Haxholdt O, Henriksen O, Dyrberg V. Effect of spinal sympathetic blockade upon postural changes of blood flow in human peripheral tissues. Acta Physiol. Scand.. 1982; 114 165-170
64 Tucker G T, Cooper S, Littlewood D, Buckley F P, Covino B G, Ueda W, Yuushuke S, Hirakawa M. Role of afferent neural input in regression of sensory paralysis during epidural analgesia. Anesth. Analg.. 1992; 74 358-361
65 Ribeiro J A, Sebastiao A M. Antagonism of tetrodotoxin- and procaine-induced axonal blockade by adenine nucleotides in the frog sciatic nerve. Br. J. Pharmacol.. 1984; 81 277-282
66 Kraynack B J, Gintautas J. Reversal of procaine conduction blockade by adenine nucleotides in vivo and in vitro. Acta Anaesthesiol. Scand.. 1982; 26 334-336
67 Collier H OJ. Cellular site of opiate dependence. Nature. 1980; 283 625-629
68 De Jong R H. Local anesthetics. Charles C Thomas, Springfield 1977: 76-85
69 Nathan P W, Sears T A. Differential nerve block by sodium-free and sodium-deficient solutions. J. Physiol. (Lond). 1962; 164 375-379
70 Spoerel W E, Thomas A, Gerula G R. Continuous epidural analgesia: experience with mechanical injection devices. Can. Anaesth. Soc. J.. 1970; 17 37-42
71 Lipfert P, Holthusen H, Arndt J O. Tachyphylaxis to local anesthetics does not result from reduced drug effectiveness at the nerve itself. Anesthesiology. 1989; 70 71-75
72 Covino B G. Ultra-long acting local anesthetic agents. Anesthesiology. 1981; 54 263-264
73 Al-Saadi D, Sneader W E. Pharmacological and microbiological evaluations of potential new long-acting local anaesthetics. Drug Res.. 1991; 41 1098-1100
74 Al-Saadi D, Sneader W E, Waton N G. Pharmacological studies on new potential local anesthetics. Pharmazie. 1994; 49 849-851
75 Butterworth J F, Strichartz G R. Molecular mechanisms of local anesthesia: a review. Anesthesiology. 1990; 72 711-734
76 Gesztes A. Topical anesthesia of the skin by liposome-encapsulated tetracaine. Anesth. Analg.. 1988; 67 1079-1081
77 Boogaerts J. Toxicity of bupivacaine encapsulated into liposomes and injected intravenously: comparison with plain solutions. Anesth. Analg.. 1993; 76 553-555
78 Lee K C, Wilder K C, Smith R L. Thermal hyperalgesia accelerates and MK-801 prevents the development of tachyphylaxis to rat sciatic nerve blockade. Anesthesiology. 1994; 81 1284-1293
79 Wilder T T, Sholas M G, Berde C B. N-Nitro-L-arginine methyl ester (L-NAME) prevents tachyphylaxis to local anesthetics in a dose-dependent manner. Anesth. Analg.. 1996; 83 1251-1255

Dr. med. Eva Kottenberg-Assenmacher

Abteilung für Anästhesiologie und Intensivmedizin Universitätsklinikum Essen

Hufelandstr. 55

D-45122 Essen